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Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Lookup NU author(s): Dr Michael Wright, Professor Judith Goodship


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Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (similar to 2.7%)(3), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance(4,5). De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations(6,7). We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings(8). Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Publication metadata

Author(s): Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Al Turki SH, Thienpont B, Mcrae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UMM, Bentham J, Berger F, Bhattacharya S, Bu'Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T, Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PEF, Keavney B, Goodship J, Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD, Hurles ME, INTERVAL Study, UK10K Consortium, Deciphering Dev Disorders Study

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2016

Volume: 48

Issue: 9

Pages: 1060-1065

Print publication date: 01/09/2016

Online publication date: 01/08/2016

Acceptance date: 24/06/2016

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/ng.3627


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Funder referenceFunder name
CHAMELEO Marie Curie Career Integration Grant
Klinisch Onderzoeksfonds
MRC Human Genetics Unit program grant
National Institute of Health Research (NIHR)
National Institutes for Health Research through the Comprehensive Clinical Research Network
National Register for Congenital Heart Defects
NIHR Cambridge Biomedical Research Centre
UK Department of Health
Competence Network for Congenital Heart Defects
Eddy Merckx Research grant
German Center for Cardiovascular Research (DZHK) partner sites Berlin, Kiel
Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research
NIHR BioResource
NIHR Blood and Transplant Research Unit in Donor Health and Genomics
NIHR Research Cambridge Biomedical Research Centre
Wellcome Trust
FS/14/51/30879British Heart Foundation Clinical Fellowship
G0800270UK Medical Research Council
HICF-1009-003Health Innovation Challenge Fund
RC12/037King Abdullah International Medical Research Center
WT098051Wellcome Trust Sanger Institute
RG/13/10/30376British Heart Foundation Programme Grant
SP/09/002British Heart Foundation